Project Summary-Abstract ?Vision is the most fundamental of our senses and it is perhaps the greatest tragedy of all when blindness robs us of this modality?. Photoreceptors are light-detecting cells initiating vision. Loss of photoreceptor leads to loss of vision. This happens in millions of Americans with hereditary retinal degenerations or age-related macular degeneration (AMD). Loss of vision is not only a personal tragedy but also a burden to the society. It is estimated that a patient with retinitis pigmentosa (RP) has an average health care cost of $7,000/year, more than that of age-matched non-RP patients. We want to develop three new in vivo imaging technologies for mapping rhodopsin, the functional and anatomic biomarker of rod photoreceptors. Based on our in-depth analysis of the clinical needs of today and in the near future for monitoring the function and anatomy of photoreceptors, we believe it will be a game changer for the diagnosis, monitoring, and treatment evaluation for retinal degenerative disorders, including hereditary retinal degeneration, AMD, and other diseases. This application has the following hypotheses: 1, Visible-light OCT (VIS-OCT) provide depth resolved information for segmentation to measure the levels and distribution of rhodopsin accurately; 2, The amount of rhodopsin can be calculated from measurements of absorbance at different wavelengths located in the rhodopsin absorption spectrum; 3, Imaging devices based on the VIS-OCT technologies could provide information to assess the levels and distribution of rhodopsin in patients. This proposal has three Specific Aims. In Aim 1, We will develop and refine three VIS-OCT based imaging technologies: a Single-Band VIS-OCT with a center wavelength of 520 nm close to the peak absorption of rhodopsin; a Tri-Band VIS-OCT that uses three bands of probing light spanning the rhodopsin absorption spectrum; and a Broad-Band VIS-OCT that uses a continuous spectrum covering the rhodopsin absorption wavelengths from 520 nm to 580 nm. The Single-Band technology will image the retina twice, once dark-adapted and then light adapted. With the Tri-Band and Broad-Band VIS- OCTs rhodopsin content will be calculated from the simultaneously acquired OCT images based on the different molar extinction coefficients of rhodopsin at different wavelengths. Since the Tri-Band and Broad- Band technologies only need to image the retina once in the dark-adapted state, it would be much more clinical friendly. In Aim 2, we will use animal models to test and fine-tune the three VIS-OCTs. In Aim 3, we will test the three OCT systems in human subjects to provide vital feedback to improve and fine-tune the hardware and software, and to establish rhodopsin ranges of normal retina and retinas of different stages of diseases. We expect to have the three systems clinically ready by the end of this project. Successful completion of the proposed experiments would add a powerful technology to ophthalmology clinics for care of patient with retinal degenerative diseases.